An optimized radiosynthesis of [18 F]FNDP, a positron emission tomography radiotracer for imaging soluble epoxide hydrolase (sEH).

In this concise practitioner protocol, the radiochemical synthesis of [18 F]FNDP suitable for human positron emission tomography studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice requirements.

Synthesis and quality control of [(18) F]T807 for tau PET imaging.

The detailed synthesis and quality control of [(18) F]T807, radiotracer for tau protein aggregate imaging, are described. The radiotracer synthesis was accomplished in an average of 48 min with an average specific activity at end-of-synthesis of over 4.4 TBq/µmole (120 Ci/µmole) and an average radiochemical yield of 32%. Compliance with all standard US Pharmacopeia Chapter <823> acceptance tests was observed.

An improved synthesis of the radiolabeled prostate-specific membrane antigen inhibitor, [(18) F]DCFPyL.

The radiosynthesis of [(18) F]DCFPyL on 2 distinct automated platforms with full regulatory compliant quality control specifications is described. The radiotracer synthesis was performed on a custom-made radiofluorination module and the Sofie Biosciences ELIXYS. The radiofluorination module synthesis was accomplished in an average of 66 minutes from end of bombardment with an average specific activity at end of synthesis (EOS) of 4.4 TBq/µmol (120 Ci/µmol) and an average radiochemical yield of 30.9% at EOS. The ELIXYS synthesis was completed in an average of 87 minutes with an average specific activity of 2.2 TBq/µmol (59.3 Ci/µmol) and an average radiochemical yield of 19% at EOS. Both synthesis modules produced large millicurie quantities of [(18) F]DCFPyL while conforming to all standard US Pharmacopeia Chapter <823> acceptance testing criteria.

Microwave-assisted radiosynthesis of [(18) F]ASEM, a radiolabeled α7-nicotinic acetylcholine receptor antagonist.

An improvement of the original radiochemical synthesis of [(18) F]ASEM, an α7-nicotinic acetylcholinergic receptor radioligand, is reported. The new procedure utilizes microwave-assisted radiofluorination. In addition, a new preparative HPLC method was developed to eliminate a chemical impurity in the final product. Quality control procedures were also enhanced to improve detection of product with enhanced resolution of potential impurities. [(18) F]ASEM was produced in 20.1 ± 8.9% non-decay corrected (NDC) yield with an average synthesis time of 57 min and an average specific radioactivity of 856 ± 332 GBq/µmol (23 ± 9 Ci/µmol).

A microwave radiosynthesis of the 4-[18F]-fluorobenzyltriphenylphosphonium ion.

The 4-[(18)F]-fluorobenzyltriphenylphosphonium cation was synthesized by a series of microwave reactions from no carrier added [(18)F]-fluoride. The microwave procedure reduced the quantity of reagents used and synthesis time when compared with the original synthesis. In addition, problematic solid phase extraction, sodium borohydride reduction by column and inconsistent yields with excessive precipitate formation during the bromination step were eliminated. The 4-[(18)F]-fluorobenzyltriphenylphosphonium cation was produced radiochemically pure in 8.3% yield with a specific radioactivity of 534.5 ± 371.4 GBq/µmole at end of synthesis.

5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice.

The radiosynthesis and in vivo evaluation of 5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole [(11)C]rac-(1), a potential PET tracer for α7 nicotinic acetylcholine receptors (α7-nAChR), are described. Syntheses of the nonradioactive standard rac-1 and corresponding desmethyl precursor 7 were achieved in several reaction steps. Radiomethylation of 7 with [(11)C]CH(3)I afforded [(11)C]rac-1 in an average radiochemical yield of 30 ± 5% (n=5) with high radiochemical purity and an average specific radioactivity of 444 ± 74 GBq/µmol (n=5). The total synthesis time was 30 min from end-of-bombardment. Biodistribution studies in mice showed that [(11)C]rac-1 penetrates the blood-brain barrier and specifically labels neuronal α7-nAChRs.

Synthesis and in vivo evaluation of (S)-6-(4-fluorophenoxy)-3-((1-[11C]methylpiperidin-3-yl)methyl)-2-o-tolylquinazolin-4(3H)-one, a potential PET tracer for growth hormone secretagogue receptor (GHSR).

The peptide hormone ghrelin mediates through action on its receptor, the growth hormone secretagogue receptor (GHSR), and is known to play an important role in a variety of metabolic functions including appetite stimulation, weight gain, and suppression of insulin secretion. In light of the fact that obesity is one of the major health problems plaguing the modern society, the ghrelin signaling system continues to remain an important and attractive pharmacological target for the treatment of obesity. In vivo imaging of the GHSR could shed light on the mechanism by which ghrelin affects feeding behavior and thus offers a new therapeutic perspective for the development of effective treatments. Recently, a series of piperidine-substituted quinazolinone derivatives was reported to be selective and potent GHSR antagonists with high binding affinities. Described herein is the synthesis, in vitro, and in vivo evaluation of (S)-6-(4-fluorophenoxy)-3-((1-[(11)C]methylpiperidin-3-yl)methyl)-2-o-tolylquinazolin-4(3H)-one ([(11)C]1), a potential PET radioligand for imaging GHSR.

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR.

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2).

Recently, A-836339 [2,2,3,3-tetramethylcyclopropanecarboxylic acid [3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide] (1) was reported to be a selective CB2 agonist with high binding affinity. Here we describe the radiosynthesis of [11C]A-836339 ([11C]1) via its desmethyl precursor as a candidate radioligand for imaging CB2 receptors with positron-emission tomography (PET). Whole body and the regional brain distribution of [11C]1 in control CD1 mice demonstrated that this radioligand exhibits specific uptake in the CB2-rich spleen and little specific in vivo binding in the control mouse brain. However, [11C]1 shows specific cerebral uptake in the lipopolysaccharide (LPS)-induced mouse model of neuroinflammation and in the brain areas with Abeta amyloid plaque deposition in a mouse model of Alzheimer's disease (APPswe/PS1dE9 mice). These data establish a proof of principle that CB2 receptors binding in the neuroinflammation and related disorders can be measured in vivo.

Synthesis and biological evaluation of novel carbon-11 labeled pyridyl ethers: candidate ligands for in vivo imaging of alpha4beta2 nicotinic acetylcholine receptors (alpha4beta2-nAChRs) in the brain with positron emission tomography.

The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), alpha4beta2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of alpha4beta2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for alpha4beta2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope (11)C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics.

N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer.

PURPOSE: Previously, we showed successful imaging of xenografts that express the prostate-specific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and the radiolabeled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine. Herein, we extend that work by preparing and testing a PSMA inhibitor of the same class labeled with fluorine-18. EXPERIMENTAL DESIGN: N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-l-cysteine ([18F]DCFBC) was prepared by reacting 4-[18F]fluorobenzyl bromide with the precursor (S)-2-[3-[(R)-1-carboxy-2-mercaptoethyl]ureido]-pentanedioic acid in ammonia-saturated methanol at 60 degrees C for 10 min followed by purification using C-18 reverse-phase semipreparative high-performance liquid chromatography. Severe combined immunodeficient mice bearing a s.c. PSMA+ PC-3 PIP tumor behind one shoulder and a PSMA(-) PC-3 FLU tumor behind the other shoulder were injected via the tail vein with either 1.85 MBq (50 microCi) of [18F]DCFBC for ex vivo biodistribution or 7.4 MBq (200 microCi) for imaging. For biodistribution, mice were sacrificed at 5, 15, 30, 60, and 120 min. Tumor, blood, and major organs were harvested and weighed, and radioactivity was counted. Imaging was done on the GE eXplore Vista small-animal PET scanner by collecting 12 consecutive 10-min frames. RESULTS: Radiochemical yield for [18F]DCFBC averaged 16 +/- 6% (n = 8) from 4-[18F]fluorobenzyl bromide. Specific radioactivities ranged from 13 to 133 GBq/micromol (350-3,600 Ci/mmol) with an average of 52 GBq/micromol (1,392 Ci/mmol; n = 6). Biodistribution and imaging studies showed high uptake of [18F]DCFBC in the PIP tumors with little to no uptake in FLU tumors. High radiopharmaceutical uptake was also seen in kidneys and bladder; however, washout of radioactivity from these organs was faster than from the PIP tumors. The maximum PIP tumor uptake was 8.16 +/- 2.55% injected dose per gram, achieved at 60 min after injection, which decreased to 4.69 +/- 0.89 at 120 min. The PIP tumor to muscle ratio was 20 at 120 min after injection. Based on the mouse biodistribution, the dose-limiting organ is the kidneys (human estimated absorbed dose: 0.05 mGy/MBq; 0.2 rad/mCi). CONCLUSION: [18F]DCFBC localizes to PSMA+-expressing tumors in mice, permitting imaging by small-animal PET. This new radiopharmaceutical is an attractive candidate for further studies of PET imaging of prostate cancer.

Synthesis and in vivo evaluation of novel PET radioligands for imaging the endothelin-A receptor.

UNLABELLED: The endothelin subtype-A (ETA) receptor is a member of a family of G-protein-coupled receptors that plays a central role in vasoconstriction, cell proliferation, and hormone production. The aim of this study was to synthesize and evaluate in vivo (11)C- and (18)F-labeled analogs of the potent and selective ETA antagonist N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940). METHODS: Protected precursors and authentic nonradioactive standards were synthesized by reductive amination and subsequent alkylation of protected aldehyde 1. Desmethyl precursor 2 was reacted with (11)C-methyl iodide followed by deprotection and high-performance liquid chromatography purification to produce (11)C-(N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,1-methylindolecarboxamide) ((11)C-BMS-5p) 3. Nitro precursor 4 was reacted with (18)F-fluoride and purified by high-performance liquid chromatography to produce (18)F-(N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,4-fluorobenzamide) ((18)F-FBzBMS) 5. Biodistribution was determined by injecting male CD-1 mice via the tail vein with either (11)C-BMS-5p 3 or (18)F-FBzBMS 5. Specific binding was determined by pretreatment with 1 mg of BMS-207940 per kilogram. PET scanning of a baboon using either (11)C-BMS-5p 3 or (18)F-FBzBMS 5 was performed at baseline and 40 min after intravenous administration of 1 mg of BMS-207940 per kilogram. RESULTS: (11)C-BMS-5p 3 was synthesized with 1.5% radiochemical yield in 36 min, with an average specific activity of 1,051 GBq/micromol (28,400 mCi/micromol; n=5) at the end of synthesis. (18)F-FBzBMS 5 was synthesized with 0.54% radiochemical yield in 130 min, with an average specific activity of 12.9 GBq/micromol (349 mCi/micromol, n=7) at the end of synthesis. In mice, the highest uptake of both radioligands was in the liver, lungs, and heart. Radioactivity in the liver washed out over time, and uptake in the lungs and heart remained relatively stable. Mice pretreated with 1 mg of BMS-207940 per kilogram showed greater than 64% specific binding in the lungs and kidneys at 60 min. Specific binding in the heart was determined to be 63% for (11)C-BMS-5p 3 and 81% for (18)F-FBzBMS 5. PET studies in a baboon showed high uptake of both radioligands in the myocardium. Between 35 and 85 min, the heart-to-blood ratio was 4.7 to 1. Pretreatment with a 1 mg/kg dose of BMS-207940 showed 85% specific binding in the myocardium at 85 min after injection. CONCLUSION: Both (11)C-BMS-5p 3 and (18)F-FBzBMS 5 bind selectively to the ETA receptor in vivo. Further development of these radioligands for imaging the ETA receptor in humans is warranted.

Positron emission tomographic studies of brain dopamine and serotonin transporters in abstinent (+/-)3,4-methylenedioxymethamphetamine ("ecstasy") users: relationship to cognitive performance.

BACKGROUND: (+/-)3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational drug and brain serotonin (5-HT) neurotoxin. Under certain conditions, MDMA can also damage brain dopamine (DA) neurons, at least in rodents. Human MDMA users have been found to have reduced brain 5-HT transporter (SERT) density and cognitive deficits, although it is not known whether these are related. This study sought to determine whether MDMA users who take closely spaced sequential doses, which engender high plasma MDMA concentrations, develop DA transporter (DAT) deficits, in addition to SERT deficits, and whether there is a relationship between transporter binding and cognitive performance. MATERIALS AND METHODS: Sixteen abstinent MDMA users with a history of using sequential MDMA doses (two or more doses over a 3- to 12-h period) and 16 age-, gender-, and education-matched controls participated. Subjects underwent positron emission tomography with the DAT and SERT radioligands, [11C]WIN 35,428 and [11C]DASB, respectively. Subjects also underwent formal neuropsychiatric testing. RESULTS: MDMA users had reductions in SERT binding in multiple brain regions but no reductions in striatal DAT binding. Memory performance in the aggregate subject population was correlated with SERT binding in the dorsolateral prefrontal cortex, orbitofrontal cortex, and parietal cortex, brain regions implicated in memory function. Prior exposure to MDMA significantly diminished the strength of this relationship. CONCLUSIONS: Use of sequential MDMA doses is associated with lasting decreases in brain SERT, but not DAT. Memory performance is associated with SERT binding in brain regions involved in memory function. Prior MDMA exposure appears to disrupt this relationship. These data are the first to directly relate memory performance to brain SERT density.

In vivo measurement of cell proliferation in canine brain tumor using C-11-labeled FMAU and PET.

INTRODUCTION: Noncatabolized thymidine analogs are being developed for use in imaging DNA synthesis. We sought to relate a labeling index measured by immunohistochemical staining bromodeoxyuridine (BUdR) technique to the uptake of (11)C 2'-fluoro-5-methyl-1-beta-d-arabinofuranosyluracil (FMAU) measured with positron emission tomography (PET) in a brain tumor model. METHODS: Adult beagles (n=8) with implanted brain tumors received [(11)C]FMAU and dynamic imaging with arterial sampling. Six dogs were then infused with BUdR (200 mg/m(2)) and sacrificed. Tumor time-activity curves (TACs) obtained from computed-tomography-defined regions of interest were corrected for partial volume effects and crosstalk from brain tissue. Tissue was analyzed for the percentage of tumor volume occupied by viable cells and by viable cells in S-phase as identified by BUdR staining. PET/[(11)C]FMAU and BUdR were compared by linear regression analysis and analysis of variance, as well as by a nonparametric rank correlation test. RESULTS: Tumor standardized uptake values (SUVs) and tumor-to-contralateral-brain uptake ratios at 50 min were 1.6+/-0.4 and 5.5+/-1.2 (n=8; mean+/-S.E.M.), respectively. No (11)C-labeled metabolites were observed in the blood through 60 min. Tumor TACs were well described with a three-compartment/four-parameter model (k(4)=0) and by Patlak analysis. Parametric statistical analysis showed that FMAU clearance from plasma into tumor Compartment 3 (K(FMAU)) was significantly correlated with S-phase percent volume (P=.03), while tumor SUV was significantly correlated with both S-phase percent volume and cell percent volume (P=.02 and .03, respectively). Patlak slope, K(FMAU) and tumor SUV were equivalent with regard to rank correlation analysis, which showed that tumor uptake and trapping of FMAU were correlated with the volume density of dividing cells (P=.0003) rather than nondividing cells (P=.3). CONCLUSIONS: Trapping of [(11)C]FMAU correlated with tumor growth rate, as measured by direct tissue analysis with BUdR in a canine brain tumor model, suggesting that [(11)C]FMAU is useful for the imaging of cell proliferation in cancers.

New synthesis and evaluation of enantiomers of 7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane as stereoselective ligands for PET imaging of nicotinic acetylcholine receptors.

A simple and efficient synthesis of nAChR antagonist (+/-)-7-methyl-2-exo-(3'-iodo-5'-pyridinyl)-7-azabicyclo[2.2.1]-heptane ((+/-)-NMI-EPB) has been developed. Both enantiomers of (+/-)-NMI-EPB were separated by semi-preparative chiral HPLC. The enantiomers manifested a substantial difference in their inhibition binding affinities ((+)-NMI-EPB, K(i)=2310, 1680 pM; (-)-NMI-EPB, K(i)=55, 68 pM). The enantiomers were stereoselectively radiolabeled with (11)C. In the distribution studies in the rodent brain [(11)C](-)-NMI-EPB specifically labeled nAChR whereas [(11)C](+)-NMI-EPB exhibited little specific binding. In the baboon PET study [(11)C](-)-NMI-EPB did not reach steady-state within 90 min post-injection suggesting that the radioligand may have some limitations for quantitative imaging.

Derivatives of (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane are potential ligands for positron emission tomography imaging of extrathalamic nicotinic acetylcholine receptors.

A series of novel racemic 7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives with picomolar in vitro binding affinity at nicotinic acetylcholine receptors (nAChRs) were synthesized and their enantiomers were resolved by semipreparative chiral HPLC. The (-)-enantiomers showed substantially greater in vitro inhibition binding affinity than the corresponding (+)-enantiomers. The compounds with best binding affinities have been radiolabeled with positron emitting isotopes 11C and 18F as potential radioligands for positron emission tomography imaging of the nAChR. In vivo enantioselectivity of the radiolabeled (-)-7-methyl-2-(5-(pyridinyl)pyridin-3-yl)-7-azabicyclo[2.2.1]heptane derivatives was observed in biodistribution studies in rodents and baboon. One of the radiolabeled compounds, (-)-7-methyl-2-exo-[3'-(2-[18F]fluoropyridin-5-yl))-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, exhibited good properties as a first practical PET radioligand for imaging of extrathalamic nAChR in baboon brain and holds promise for further investigation for human studies.

6-Chloro-3-(((1-[11C]methyl)-2-(S)-pyrrolidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine ([11C]JHU85270), a potent ligand for nicotinic acetylcholine receptor imaging by positron emission tomography.

6-Chloro-3-((1-methyl)-2-(S)-pyrrolidinyl)methoxy)-5-(2-fluoropyridin-4-yl)pyridine (JHU85270), a novel high-affinity ligand for the alpha4beta2 nicotine acetylcholine receptor (nAChR) (K(i)=86, 115 pM; K(i)(JHU85270)/K(i)(epibatidine)=1.7) with a log D(7.4)=1.6 was synthesized in 56% overall yield. [(11)C]JHU85270 was synthesized from [(11)C]-methyl iodide and the corresponding normethyl precursor. The average time of radiosynthesis, purification, and formulation was 37 min from the end of bombardment. The average radiochemical yield of [(11)C]JHU85270 was 37%+/-3% (non-decay corrected). The average specific radioactivity was 398+/-165 GBq/micromol (10750+/-4468 mCi/micromol) and the radiochemical purity was greater than 99%.

Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography.

Aggregates of tau and beta amyloid (Aß) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aß plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.

Characterization of uptake of the new PET imaging compound 18F-fluorobenzyl triphenyl phosphonium in dog myocardium.

UNLABELLED: 18F-Labeled p-fluorobenzyl triphenyl phosphonium cation (18F-FBnTP) is a member of a new class of positron-emitting lipophilic cations that may act as myocardial perfusion PET tracers. Here, we characterize the 18F-FBnTP uptake and retention kinetics, in vitro and in vivo, as well as the myocardial and whole-body biodistribution in healthy dogs, using PET. METHODS: Time-dependent accumulation and retention of 18F-FBnTP in myocytes in vitro was studied. Seven anesthetized, mongrel dogs underwent dynamic PET scans of the heart after intravenous administration of 126-240 MBq 18F-FBnTP. In 4 of the 7 dogs, at the completion of a 60-min dynamic scan, whole-body scans (4 bed positions, 5-min emission and 3-min transmission per bed) were acquired. Arterial blood samples were collected at 0, 5, 10, 20, 30, and 60 min after administration, plasma activity was counted, and high-performance liquid chromatographic analyses for metabolites were performed. The extent of defluorination was assessed by measuring 18F-FBnTP bone uptake in mice, compared with 18F-fluoride. RESULTS: The metabolite fraction comprised <5% of total activity in blood at 5 min and gradually increased to 25% at 30 min after injection. In vivo, 18F-FBnTP myocardial concentration reached a plateau level within a few minutes, which was retained throughout the scanning time. In contrast, activity in the blood pool and lungs cleared rapidly (half-life = 19.5 +/- 4.4 and 30.7 +/- 11.6 s, respectively). Liver uptake did not exceed the activity measured in the myocardium. At 60 min, the uptake ratios of left ventricular wall to blood, lung, and liver (mean of 7 dogs) were 16.6, 12.2, and 1.2, respectively. Summation of activity from 5 to 15 min and from 30 to 60 min after injection produced high-quality cardiac images of similar contrast. Circumferential sampling and a polar plot revealed a uniform distribution, near unitary value, throughout the entire myocardium. The mean coefficient of variance, on 30- to 60-min images along the septum-to-anterior wall and the apex-to-base axes was 7.58% +/- 1.04% and 6.11% +/- 0.89% (mean +/- SD; n = 7), respectively, and on 5- to 15-min images was 7.25% +/- 1.43% and 6.12% +/- 1.88%, respectively. 18F-FBnTP whole-body distribution was highly organ specific with the kidney cortex being the major target organ, followed by the heart and the liver. CONCLUSION: 18F-FBnTP is a promising new radionuclide for cardiac imaging using PET with rapid kinetics, uniform myocardial distribution, and favorable organ biodistribution.

11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors.

UNLABELLED: The development of the radioligands for PET imaging of the cerebral cannabinoid receptor (CB1) is of great importance for studying its role in neuropsychiatric disorders, obesity, and drug dependence. None of the currently available radioligands for CB1 are suitable for quantitative PET, primarily because of their insufficient binding potential (BP) in brain or low penetration through the blood-brain barrier (BBB). The goal of this study was to evaluate 11C-JHU75528, an analog of the selective CB1 antagonist rimonabant, in vivo as a potential CB1 radioligand for PET. METHODS: The brain regional distribution and pharmacology of 11C-JHU75528 have been evaluated in vivo in mice (dissection) and baboons (PET). RESULTS: 11C-JHU75528 readily entered the mouse and baboon brain and specifically and selectively labeled cerebral CB1 receptors. The ratio of striatum to brain stem in mice and the binding potential (BP) in the baboon putamen were 3.4 and 1.3-1.5, respectively. The specific binding of 11C-JHU75528 in vivo was blocked by preinjection of nonlabeled JHU75528. Administration of rimonabant (1 mg/kg, intravenously) also blocked the specific binding of 11C-JHU75528 in the mouse and baboon brain, whereas various central noncannabinoid drugs did not significantly reduce the 11C-JHU75528 binding in the mouse brain. 11C-JHU75528 formed several hydrophilic metabolites, but only a minute fraction of metabolic radioactivity penetrated the BBB. CONCLUSION: 11C-JHU75528 holds promise as a radiotracer with suitable imaging properties for quantification of CB1 receptors in the human brain.